1. Field of the Invention
The invention is directed to a new process for synthesizing delta-amino levulinic acid (also known as 5-aminolevulinic acid) as its hydrochloride salt (DALA. HCl), starting from levulinic acid. In particular, the invention method uses sodium diformylamide as a highly reactive and readily accessible reagent for the amination of the C-5 position of methyl 5-bromolevulinate. This process generates an N,N-diformylamido derivative of the levulinate ester that is hydrolyzed with aqueous hydrochloric acid to generate DALA. HCl as a crystalline solid.
2. Description of the Prior Art
Delta-aminolevulinic acid in the salt form (DALA. HCl) is known to have potent herbicidal activity against a broad spectrum of weeds and plants, and is also the subject of studies for use as an antitumor compound in humans. The known synthesis of DALA. HCl that are based on levulinic acid as a starting material are difficult to carry out because of the use of undesirable reagents that are either very toxic or that are not atom economical. In addition, in the currently known synthesis of DALA. HCl, a hazardous chemical step is required to "deprotect" the resulting amino group.
U.S. Pat. No. 5,380,935 discloses a process for preparing 5-aminolevulinic acid or a salt thereof, which comprises reacting furfurylamine, of which the amino group has been protected, with an oxygen molecule under irradiation by light in the presence of a sensitizer, hydrogenating the resulting compound in the presence of a metallic catalyst, and hydrolyzing the hydrogenated compound.
A process for preparation of N-acyl-derivatives of 5-amino levulinic acid as well as the hydrochloride of the free acid is disclosed in U.S. Pat. No. 5,344,974. The process condenses 5-hydroxymethyl furfural with a nitrile in acid solution and the N-acyl aminomethyl furfural compound obtained is converted by photooxidation into a N-acyl-5-aminomethyl-5-hydroxydihydro-2,5-furan-2-one and the latter is reduced with zinc in acetic acid under ultrasonic treatment to N-acyl-5-aminolevulinic acid and by acid hydrolysis the 5-aminolevulinic hydrochloride is obtained.
U.S. Pat. No. 5,284,973 disclose a method of making an acid addition salt of delta-aminolevulinic acid by reacting tetrahydrofurfurylamine with phthalic anhydride under an anhydrous condition to introduce a phthalic group which protects the amino group of tetrahydrofurfuryl amine to give N-tetrahydrofurfuryl pthalimide, carbon atoms of the first-and fourth-positions of the obtained N-tetrahydrofurfurylpthalimide are oxidized at 80.degree. C. using sodium periodate as an oxidizing agent and ruthenium chloride hydrate as a catalyst to yield 5-phthalimidolevulinic acid, and the protecting group of the 5-phthalimidolevulic acid is deprotected using an acid to prepare an acid addition salt of delta-aminolevulinic acid.
A method of producing delta-aminolevulinic acid hydrochloride is disclosed in U.S. Pat. No. 3,846,490. The method comprises acylating hippuric acid with monosuccinate acyl-chloride in the medium of 65-picoline, subjecting the thus-obtained c-acyl derivative to hydrolysis and isolating the final product.
U.S. Pat. No. 4,325,877 discloses a method of producing delta-aminolevulinic acid by the use of intermediates of bromoketoesters. However, this patent makes use of metal azides in the amination step to convert the bromoketoesters into delta-aminolevulinic acid.
The foregoing prior art methods do not make use of levulinic acid as a starting material for the synthesis of delta-aminolevulinic acid. The starting materials in these methods are acrylic acid ester, 5-hydroxymethyl-furfural, tetrahdyro-furfurylamine, furfurylamine, and hippuric acid.
There is a need in the art of preparing delta-amino levulinic acid to avoid the difficulty of carrying out the process by relying on the use of undesirable reagents that are either very toxic or not atom economical. There is a further need when preparing delta-aminolevulinic acid to avoid the hazardous chemical step normally required to "deprotect" the resulting amino group.